3. CONTENTS
DEFINITION OF DISTRIBUTION
EXPLANATION
DRUG DISTRIBUTION IS NOT UNIFORM
• REASON OF NON-UNIFORMITY OF DRUG
DIDTRIBUTION
FACTORS AFFECTING THE DRUG
DISTRIBUTION
• FACTORS RELATED TO THE BODY
• FACTORS RELATED TO THE DRUG
REFRENCES
4. DEFINITION OF DRUG
DISTRIBUTION
Distribution in pharmacology is a
branch of pharmacokinetics which
describes the reversible transfer of a
drug from one location to another within
the body.
for example, fat, muscle, and brain
tissue
Drug distribution refers to the
movement of a drug to and from the
blood and various tissues of the body.
5.
6. EXPLANATION
Once a drug enters into systemic circulation
by absorption or direct administration, it must
be distributed into interstitial and
intracellular fluids.
The distribution of a drug between tissues is
dependent on vascular permeability, regional
blood flow, cardiac output and perfusion rate
of the tissue and the ability of the drug to
bind tissue and plasma proteins and its lipid
solubility
pH partition plays a major role as well).
7. DRUG DISTRTIBUTION IS
NOT UNIFORM PROCESS
• Distribution of drugs throughout the body
fluid is not equal.
• Each organ or tissue can receive
different doses of the drug and the
drug can remain in the different organs
or tissues for a varying amount of time.
• Distribution of drug throughout the
body is not uniform , because the
different tissues receive the drug from
plasma at different rates and different
extents.
8. REASON FOR UNEQUAL
DISTRIBUTION OF DRUG
• The reason for unequal
distribution of drug are as
follows:
1. Drug factors
2. pH of the media
3. Regional blood flow
4. Drug binding…protein / tissue
5. Membranes
9. FACTORS AFFECTING THE
DRUG DISTRIBUTION
Factors related to the body Factors related to the drug
• Lipid solubility
• Molecular size
• Degree of ionization
• Cellular binding
• Duration of action
• Therapeutic effects
• Toxic effects
• Vascularity
• Transport mechanisms
• Blood barriers
• Placental proteins
• Transport binding proteins
• Free and bound forms of
drug
• Drug interactions
• Disease states
• Drug reservoirs
• Volume of distribution
10. 1 . FACTORS RELATED
TO DRUG
LIPID SOLUBILITY:
Greater the lipid solubility, more is the distribution
and vice versa.
MOLECULAR SIZE:
Larger the size, less is the distribution. Smaller
sized drugs are more extensively distributed.
DEGREE OF IONIZATION:
• Drugs exist as weak acids or weak bases when
being distributed.
• Drugs are trapped when present in the ionized
form, depending upon the pH of the medium.
• This fact can be used to make
the drug concentrated in specific compartments.
11. CONT..
CELLULAR BINDING:
Drugs may exist in free or bound form. Bound
form of drugs exists as reservoirs. The free and
bound forms co-exist in equilibrium. Cellular
binding depends on the plasma binding
proteins.
Tissue binding
Different drugs have different affinity for
different cells. All cells do not bind the
same drugs.
DURATION OF ACTION:
The duration of action of drugs is prolonged by
the presence of bound form while the free
form is released. This leads to a longer half
life and duration of action of drug
12. CONT..
THERAPEUTIC EFFECTS:
Bisphosphonate compounds bind with the
bone matrix cells and strengthen them. They
are used in the treatment of osteoporosis.
TOXIC EFFECTS
• The toxic effects of a drug are dose-
dependent and can affect an entire system
as in the CNS or a specific organ such as the
liver
• Chloroquine can be deposited in the retina.
• Tetracycline can bind the bone material. It
may also get bound to the enamel of the
teeth.
13. Lipid solubility of drug
Molecular size of drug
Cellular binging of drug
Duration of
action of drug
14. 2 . FACTORS RELATED TO
THE BODY
VASCULARITY:
• Most of the blood passes through the highly
perfused organs (75%) while the remaining
(25%) passes through the less profuse areas.
Therefore, most of the drugs go first to the
highly perfuse areas. They may get bound
to these organs. They are then redistributed
to the less perfuse areas like the skin and
the skeletal muscles. This phenomenon is
common among the lipid soluble drugs.
• Example includes thiopentone sodium which
is used as general anesthetic which causes
hypnosis.
15. CONT..
TRANSPORT
MECHANISM:
Different drugs are taken up by
different compartments of the
body differently. Lipid soluble drug
move by passive transport which is
nonspecific. Active transport
occurs only where carrier proteins
are present
BLOOD BARRIERS:
Different blood barriers exist.
Blood brain barrier is present
because of the delicacy of nervous
tissue to avoid chemical insult to
the brain.
16. CONT…
PLACENTAL BARRIERS:
• Trophoblastic tissue separates maternal
blood from fetal blood. Different
transporters are present. Efflux
transporters cause efflux back of
the drugs from the fetus to the mother.
PLASMA BINDING
PROTEIN:
Many proteins exist in the plasma.
Plasma binding proteins include:
• Albumins
• Globulins
• Glycoproteins
• lipoproteins
17. CONT..
FREE AND BOUND FORMS OF
DRUG:
• When drug enters the body, it exists in:
• Free form
• Bound form
• free forms are metabolized and excreted because
they can cross the glomerular membrane. Free forms
of drugs are therapeutically active.
• Bound forms of drugs act as a reservoir. They are not
metabolized or excreted and do not have therapeutic
or toxic effect. When the free form is used up, drug is
released from the reservoirs. Thus both forms exist in
equilibrium.
18. CONT..
DRUG INTERACTIONS:
• If a number of drugs are simultaneously
given, or drugs interact with endogenous
substances, one drug can be displaced by
another.
• Example includes interaction of
sulphonamide with bilirubin, with the
result that bilirubin is displaced which may
cause kernicterus in babies
• Drug interactions occur if both drugs bind
to same protein and depend on:
• Affinity
• Concentration
• Volume of distribution
• therapeutic index
19. CONT..
DISEASE STATES:
• Different diseases affect the
distribution of drugs. Renal
diseases cause hypoalbuminemia.
Due to less proteins, toxic levels of
free drugs may be present. Uremic
by-products are also produced
which compete with drugs
• Hepatic diseases cause decreased
synthesis of proteins causing
hypoalbuminemia. Free drugs may
be present in toxic levels and
bilirubin by products increase as
well.
20. CONT..
DRUG RESERVOIRS
• Drugs are stored and are released slowly which
affects their pharmacokinetics and
pharmacodynamics. Drug reservoirs include:
• Plasma proteins
• Liver
• Adipose
• Bone
• Placenta
• Breast milk
• Transcellular fluid reserves
• Other body tissues- eye, kidneys, skeletal muscles,
skin
21. CONT..
VOLUME OF
DISTRIBUTION:
• The apparent or hypothetical volume in
the body into which a drug distributes.
• Vd means the amount of fluid in which
the administered drug is distributed.
• The Volume of distribution (VD), also
known as Apparent volume of
distribution, is used to quantify the
distribution of a drug between plasma
and the rest of the body after oral or
parenteral dosing.
•
22. Formula for volume of distribution
Dose of the drug given (Q)
• Vd= --- ----------------------------------------------
Concentration of drug in plasma (Cp)
It is called as Apparent Volume because
all parts of the body equilibrated with
the drug do not have equal
concentration
CONT..
Example includes thiopentone sodium which is used as general anesthetic. When given, it goes to the brain producing its effects. It is then redistributed to the less profused organs. Because of high lipid solubility, it is accumulated in the fatty tissue for longer duration. Thus the clearance of the drug is slow, producing prolonged period of drowsiness (up to 24 hours).
Transporters:
Certain efflux pumps or transporters exist through which drug can be effluxed as well. Example includes p-glycoprotein.
Disruption:
Disruption of barrier may occur, e.g. by inflamed meningitis. Drugs may pass which might be toxic as well as beneficial i.e. during meningitis penicillin can pass which has beneficial effects.
a. Albumin
Albumin is the most abundant plasma protein. It has higher affinity for acidic drugs but the capacity is low. Only two sites are present for binding drug molecules.
However, albumin can bind a large number of basic drugs but has lower attractive forces. Its capacity for binding basic drugs is more but the affinity is less.
b. Globulins
Globulins can bind hormones, vitamins, etc.
c. Glycoproteins
Alpha glycoproteins mainly bind basic drugs. Their levels are increased during stress, trauma and surgery. It is during these times that their more amounts are required.
d. Lipoproteins
Lipoproteins also bind some drugs.
Affinity
Higher the affinity of the drug, more easily can it displace the other drug.
b. Concentration
Higher concentration drug can displace the lower concentration drugs.
This phenomenon might be of consequence in the following situations:
a. Volume of Distribution:
The volume into which the drug is distributed is known as the volume of distribution. If drug can be distributed to different body compartments, it is diluted when goes to the different compartment. If the drug has a small volume of distribution, it stays in the same compartment producing toxic effects. (Explained separately)
Toxic effects are produced when more drug is present in free form than usual.
